Parasympathetic activation by vagus nerve stimulation

ABSTRACT

The vagus nerve and branches of the vagus nerve are stimulated below the laryngeal nerve branch bifurcation in order to induce desired parasympathetic responses, such as decreased heart rate, without also triggering any adverse sympathetic responses. Stimulating surfaces of an open field bipolar electrode are positioned on or inserted through the pleural membrane overlying the vagus nerve at a location having substantially no cardiac sympathetic fibers adjacent to the vagus nerve. The open field bipolar electrodes can be securable-wire, needle, plate, or any other type of electrode suitable for being secured to the pleural membrane using one or more fastening mechanisms. Electrical stimuli are generated by a stimulator connected to the stimulating surfaces of the open field bipolar electrode by one or more leads.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/328,386, filed Jan. 23, 2017, which is a U.S. national phase ofInternational Patent Application No. PCT/US2015/041839, filed Jul. 23,2015, which claims priority to and the benefit of the filing date ofU.S. Provisional Patent Application No. 62/028,108, filed Jul. 23, 2014.The entirety of each of these applications is incorporated herein byreference for all purposes.

BACKGROUND Field of the Invention

The present invention is generally related to treatment of heart failureand is more specifically related to vagus nerve stimulation to induceparasympathetic activation.

Related Art

Congestive heart failure (CHF) is characterized by a sustained decreasein the heart's pumping ability usually due to ventricular contractiledysfunction. CHF results in decreased blood delivery to the body and anaccumulation of blood on the venous side of the circulatory system. Oneconsequence of CHF is long term deleterious effects on cardiac functioncaused by an activation of both the sympathoadrenal and therenin-angiotensin-aldosterone system. CHF also causes drops in vagal andparasympathetic activities, leading to a decrease in the release ofacetylcholine and activation of cardiac muscarinic receptors. On the onehand, the activation of cardiac muscarinic receptors generallysuppresses atrial pacemaker activity, slows the rate of excitationspreading from the atrium to the ventricles, and decreases thecontractility and conduction rate of both the atrium and the ventricle.Meanwhile, the benefits of vagal activity are largely diminished, suchas its antagonistic effects on the release of catecholamines fromsympathetic nerve terminals and anti-inflammatory immune responses.

The vagus nerve is part of the automatic nervous system that controlsinvoluntary bodily functions, including heart rate. Patientsexperiencing CHF exhibit a lack of parasympathetic input to the heart.Thus, vagal nerve stimulation has proven to be an effective treatmentfor heart failure. In one recent clinical study conducted by Schwartz,the right vagus nerve was stimulated using a cuff electrode. Thetreatment included application of electric pulse stimulation at anaverage frequency of 2 to 4 Hertz and with currents ranging from 4 to 5mA to achieve a reduction in heart rate. The electric pulses weredelivered during the refractory period of the ventricles using higherfrequency pulse trains. On the one hand, the Schwartz study reported anumber of positive outcomes, including improvements in patient symptomsbased on New York Heart Association's (NYHA) functional classificationsystem. Treated patients, for instance, were able to sustain greaterlevels and extent of physical activities, such as longer periods ofwalking. Results of the study additionally demonstrated improved leftventricular end-systolic volume and end-diastolic volume in patients 3,6, and 12 months post-implant. However, the study also revealed a numberof negative side effects, particularly ones associated with theselection of treatment site.

In the Schwartz study, vagal nerve stimulation was performed in the neckregion of the participating patients, which is consistent with theprevailing practice. In human beings, vagal nerve stimulation istypically performed by applying electrical stimulation to the portion ofthe vagus nerve that traverses the neck region. The neck region is acommon stimulation site because the human vagus nerve tends to be moreaccessible for electrical stimulation by conventional electrodes in thatparticular region. Vagal nerve stimulation in the neck obviates riskysurgical procedures and can be performed under local anesthesia.However, vagal nerve stimulation in the neck can also cause a litany ofnegative side effects. As was reported in the Schwartz study,stimulating the vagus nerve in the neck region can cause transienthoarseness, coughing, and pronounced sensation of electrical stimulationand discomfort. Consequently, for patients treated according to theSchwartz methodology, the duration of each continuous stimulation periodis limited.

SUMMARY

To reduce or to avoid the side effects of conventional treatmentmethods, the apparatus and method described herein are directed towardstimulation of the vagus nerve at a select location other than the neckregion. Applications of the apparatus and methods described herein arehighly beneficial for patients with chronic heart failure and are alsobeneficial during open heart surgery, a period when vagalparasympathetic effects on the heart are reduced. In some embodiments,cardiac branches of the vagus nerve are stimulated below the laryngealnerve bifurcation, an area of the vagus nerve located in the right upperchest below the branching point of the recurrent laryngeal nerve. Insome embodiments, stimulation is applied to the vagus nerve and caudalcardiac branch of the vagus nerve below the laryngeal nerve branchbifurcation from the vagus nerve. Advantageously, stimulating the vagusnerve and branches of the vagus nerve below the laryngeal nerve branchbifurcation has been shown to slow the heart rate with minimal sideeffects. For example, stimulating the branches of the vagus nerve belowthe laryngeal nerve bifurcation results in parasympathetic activationwithout disturbing nearby sympathetic nerve fibers and triggering anyadverse sympathetic responses (e.g., increased heart rate). In addition,some embodiments of the apparatus and method described herein aredirected toward a minimally invasive means of implanting an electrode inthe upper thorax. For example, vagal stimulation is performed withoutthe placement of a cuff around the nerve (i.e., cuff electrode).

Instead, in some embodiments, an open field electrode is placed on thepleural membrane overlying the vagus nerve or through the pleuralmembrane overlying the vagus nerve. In humans, there is minimalmusculature where the vagus nerve is located in the upper thorax and thevagus nerve and its branches are isolated from sensory nerves by thetracheal and lungs allowing for vagal stimulation without discomfort.Thus, in embodiments where the vagus nerve is stimulated in the upperthorax, open field electrodes are superior since open field electrodesentail a less complicated and less invasive implantation procedure thancuff electrodes. However, use of an open field electrode can stimulatenearby sympathetic nerve fibers and trigger adverse sympatheticresponses (e.g., increased heart rate). Some embodiments of theapparatus and method described herein are directed toward the use of aneedle type electrode. In some embodiments, vagal stimulation in theupper thorax is performed using a securable-wire electrode. Thesecurable-wire electrode is akin to the needle electrodes used inearlier studies but offers more clinical utility as it can be placedcloser to the vagus nerve. This is a particularly useful feature incases where there is copious fat surrounding the nerve or where thebranches of the vagus nerve are distant from the pleural membrane. Inaddition, a securable-wire electrode can be attached more easily to thepleural membrane.

Other features and advantages of the present invention will become morereadily apparent to those of ordinary skill in the art after reviewingthe following detailed description and accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

The structure and operation of the present invention will be understoodfrom a review of the following detailed description and the accompanyingdrawings in which like reference numerals refer to like parts and inwhich:

FIG. 1 is a diagram illustrating an example apparatus for stimulatingthe vagus nerve according to an embodiment;

FIG. 2A is a diagram illustrating an example bipolar electrode leadaccording to an embodiment;

FIG. 2B is a diagram illustrating an example bipolar electrode leadhaving an insertion needle according to an embodiment;

FIG. 2C is a diagram illustrating an example bipolar electrode leadhaving a cap according to an embodiment;

FIG. 3A is a diagram illustrating an example placement of stimulatingsurfaces near the vagus nerve according to an embodiment;

FIG. 3B is a diagram illustrating an example placement of stimulatingsurfaces near the vagus nerve according to an embodiment;

FIG. 3C is a diagram illustrating an example placement of stimulatingsurfaces near the vagus nerve according to an embodiment;

FIG. 3D is a diagram illustrating an example placement of stimulatingsurfaces near the vagus nerve according to an embodiment;

FIG. 4 is a diagram illustrating an example of the upper portion of theglossopharyngeal, vagus, and accessory nerves according to anembodiment; and

FIG. 5 is a block diagram illustrating an example wired or wirelessprocessor enabled device that may be used in connection with variousembodiments described herein.

DETAILED DESCRIPTION

Certain embodiments disclosed herein provide for an apparatus and amethod of stimulating the vagus nerve in the upper thorax in order tocause parasympathetic activation in patients suffering from heartfailure. For example, the vagus nerve trunk or alternatively branches ofthe vagus nerve are stimulated below the laryngeal nerve bifurcationusing open field electrodes (e.g., small plate electrode, epimysialelectrode, fascial electrode, needle electrode, securable-wireelectrode, etc.). After reading this description it will become apparentto one skilled in the art how to implement the invention in variousalternative embodiments and alternative applications. However, althoughvarious embodiments of the present invention will be described herein,it is understood that these embodiments are presented by way of exampleonly, and not limitation. As such, this detailed description of variousalternative embodiments should not be construed to limit the scope orbreadth of the present invention as set forth in the appended claims.

Introduction

Use of isolated field electrodes (e.g., cuff electrode) for vagalstimulation in the neck area has many drawbacks. The inventors haverecognized that vagal stimulation below the laryngeal nerve bifurcationprovides substantial improvement of many of these drawbacks. However,implantation of an isolated field electrode below the laryngeal nervebifurcation is undesirable. Accordingly, the inventors have recognizedthat use of an open field electrode (e.g., small plate electrode,epimysial electrode, fascial electrode, needle electrode, securable-wireelectrode, etc.) is superior for implantation because open fieldelectrodes entail a less complicated and less invasive implantationprocedure. However, use of an open field electrode below the laryngealnerve bifurcation may cause undesirable stimulation of nearby cardiacsympathetic nerve fibers that come from the sympathetic chain ganglia(e.g., from the cervical and stellate sympathetic ganglia) and therebytrigger adverse sympathetic responses such as increased heart rate. Theinventors have therefore also recognized that the specific implantationlocation of the open field electrode (specifically, the simulatingsurfaces of the open field electrode) is paramount for realizing thesignificant benefits of parasympathetic activation while minimizing thesignificant drawbacks of adverse sympathetic responses triggered bystimulation of nearby cardiac sympathetic nerve fibers. While thespecific location may vary from patient to patient, the optimalimplantation location is generally between 1 cm and 10 cm below (caudalor distal to) the laryngeal nerve bifurcation from the vagus nerve.

FIG. 1 is a diagram illustrating an example apparatus for stimulatingthe vagus nerve 130 according to an embodiment. In some embodiments, theapparatus is used to stimulate the vagus nerve 130 in the upper thorax.For example, the apparatus can be used to stimulate the vagus nerve 130below the laryngeal nerve bifurcation. The portion of the vagus nerve130 that is stimulated may be the main vagus nerve trunk or may be oneor more branches of the vagus nerve 130.

As shown in FIG. 1, apparatus includes a stimulator 100 and a bipolarstimulating electrode 110, which may comprise one or more leads 112A,112B each having one or more stimulating surfaces 120 arranged in abipolar configuration. In some embodiments, the leads 112A, 112B arecoated with an insulating material, such as Teflon® or any otherappropriate material. The stimulating surface 120 on each electrode maycomprise an uncoated or uninsulated portion of the electrode. Inalternative embodiments, the stimulating surface 120 may have a varietyof shapes such as a rectangle, an arrow/point, an oval, a circle, or thelike. Advantageously, the shape of the stimulating surface 120 may beselectively optimized for the location in which the stimulating surface120 is deployed (e.g., on an outer surface of the pleural membrane orbetween the vagus nerve and an inner surface of the pleural membrane).Each of the two leads 112A, 112B comprising the bipolar stimulatingelectrode is attached at a proximal end to the stimulator 100 and inelectrical communication with the stimulator 100. In an embodiment, thestimulator 100 is located inside the body. In an alternative embodiment,the stimulator 100 is located outside of the body.

The stimulator 100 comprises a power source for generating electricalstimuli and a memory 95 for storing operating parameters andinstructions and the like. The stimulator may include communicationinterfaces for receiving instructions from a separate device via a wiredor wireless communication link. The power source may be internal (e.g.,battery) or external (e.g., power supply connected to an external powersource such as an electrical grid). The stimulator 100 comprises aprocessor configured to control the operation of the stimulator 100 inaccordance with predetermined instructions or instructions receiveddynamically in real time. An example hardware embodiment of stimulator100 is later described with respect to FIG. 5.

FIG. 1 illustrates that the stimulating surfaces 120 in the bipolarconfiguration are placed within close proximity of the vagus nerve 130.In some embodiments, the electrode 110 comprises an open fieldelectrode. As such, in some embodiments, the stimulating surfaces 120can be positioned without an isolating cuff. According to theembodiments describe herein, the stimulating surfaces 120 can be placedadjacent to the vagus nerve 130 by attaching or securing the electrodesto an outer surface of the pleural membrane in a number of differentways. For example, the leads 112A, 112B can be secured using sutures,self-securing barbs, surgical glue, mesh, corkscrew wire, or any otherappropriate fastening mechanisms. Securing means that attach theelectrode 110 to physical structures on or near the vagus nerve 130 canbe applied at one or more locations along the leads 112A, 112B andstimulating surfaces 120 of the electrode 110.

In some embodiments, apparatus 100 is used to stimulate branches of thevagus nerve 130 in the upper-thorax as therapy for patients sufferingfrom heart failure. In some embodiments, stimulating parameters,including frequencies that range from 4 Hertz to 20 Hertz, are used inorder to induce the desired vagal effects, such as a decrease in heartrate. Stimulating the vagus nerve 130 with an excessively large currentis known to cause negative side effects (e.g., paraspinal musclestimulation). Additionally, high stimulating currents may inducesupraventricular arrhythmia. In some embodiments, the main vagus nervetrunk or branches of the vagus nerve 130 are stimulated according tostimulating parameters that include current amperage ranging from 1 mAto 12 mA. In some embodiments, a stimulating pulse duration of 300 μs isoptimal for stimulating the small parasympathetic fibers in the vagusnerve or its branches that innervate the heart. In some embodiments, thestimulating pulse duration can range from 200 μs to 1000 μs. In someembodiments, duty cycles of stimulation are used in order to maintaineffective stimulation. In one embodiment, the duty cycle can comprise a10 second ON period and a 5 second OFF period. In some embodiments, theduty cycle can include a continuous ON period of up to 24 hours and a 1to 2000 second OFF period for recovery.

In one embodiment, stimulation of the vagus nerve 130 is conducted toinduce two to ten beats per minute of heart rate slowing. For example,initial stimulation may be conducted at a low frequency (e.g., 4 Hz) anda low current (e.g., 1 mA) for a low duration (e.g., 200 μs) and if thedesired reduction in heart rate is not achieved, higher frequencies,current and duration may be employed singularly or in any combinationuntil the desired heart rate reduction is achieved.

FIG. 2A is a diagram illustrating an example lead 112 of a bipolarelectrode 110 according to an embodiment. In alternative embodiments,bipolar electrode 110 comprises an open field electrode, a wireelectrode, a needle electrode, an epimysial electrode, a fascialelectrode or any other type of electrode that can be configured to bepositioned on or near the vagus nerve 130. Although only a single lead112 is shown in FIG. 2A for the sake of simplicity, it will beunderstood that one or more leads 112 may be employed, with each lead112 being electrically coupled to the stimulator 100.

According to the embodiment illustrated in FIG. 2A, the lead 112comprises a conducting wire 160 that is at least partially surrounded byan insulating surface 170. The lead 112 additionally comprises one ormore stimulating surfaces 120 in an exposed area 180 where theconducting wire 160 is not covered by the insulating surface 170. Theexposed area 180, although shown in an interior portion of the lead 112,can alternatively be positioned at the distal end of the lead 112. In anembodiment having more than one stimulating surface 120 on an individuallead 112, the plural stimulating surfaces 120 may all be positioned inan interior portion of the lead 112 or one of the stimulating surfaces120 may be positioned at the distal end of the lead 112 furthest awayfrom the stimulator 100.

In some embodiments, portions of the leads 112 are insulated by theinsulating surface 170 while other portions of the leads 112 are notinsulated and create exposed areas 180. In some embodiments, the exposedareas 180 of the lead 112 comprise stimulating surfaces 120. Forexample, each of the leads 112 may contain at least one stimulatingsurface 120 in an exposed area 180. However, it may be desirable ornecessary in some cases for each lead 112 to have multiple (i.e., two ormore) stimulating surfaces 120. In some embodiments, the leads 112 andthe stimulating surfaces 120 are positioned at a desired distance apartfrom one another. For example, the stimulating surface 120 on a firstlead can be positioned 1 mm to 5 mm away from the stimulating surface120 on a second lead.

Furthermore, in some embodiments, the stimulating surfaces 112 on theleads 112 are relatively small in size. For example, in order to achievethe desired parasympathetic effects, the vagus nerve and particularlythose fibers that innervate the heart, must be stimulated with aconcentrated electric current. In an embodiment where the electrode 110comprises an open field electrode, the stimulating surfaces 120 areadvantageously relatively small in size in order to produce high chargeinjection densities and thereby stimulate the vagus nerve 130 with thelowest possible current. For example, the stimulating surfaces 120 insuch an embodiment can be between 0.5 mm to 5 mm long and 0.5 mm wide to5 mm wide (e.g., an area of 0.25 mm² to 25 mm²). In alternativeembodiments, the area of the simulating surfaces 120 may be smaller, forexample a length between 0.5 mm to 5 mm long and the width from 0.5 mmto 1.5 mm wide (e.g., an area of 0.25 mm² to 7.5 mm²). In oneembodiment, the stimulating surfaces 120 areas are cross-sectional areasand the actual area of exposed stimulating surface would be much greaterif multi-stranded wire were used as the stimulating surface 120.

In alternative embodiments, the stimulating surfaces 120 are 0.5 mm to1.5 mm in length and 0.5 mm to 1.5 mm in width. In other embodiments,the stimulating surfaces 120 are 1 mm to 2 mm in length and 1 mm to 2 mmin width. Advantageously, a small area of the stimulating surface 120generates a contained electric field and avoids the negativeconsequences associated with spreading the electric field.

According to the embodiments described herein, conducting wire 160 canbe made of any appropriate conductive material that is both corrosionand fracture resistant (e.g., platinum). In other words, the stimulatingsurfaces 120 at the exposed areas 180 of the leads 112 can be made ofany conductive material that is resistant to corrosion and fracture,such as platinum, 316 LVM stainless steel, or any suitable equivalent.In some embodiments, the insulating surface 170 surrounding theconducting wire 160 may comprise a single enclosure such as a tube. Insome embodiments, post insertion, leads 112 are secured to the pleuralmembrane 200 surrounding the vagus nerve 130. In some embodiments, leads112 are secured to the pleural membrane 200 at its entry point and exitpoint through the pleural membrane 200. In some embodiments, the leads112 can be secured to the pleural membrane 200 using any appropriatefastening mechanisms, including but not limited to surgical clips,sutures, barbs, corkscrew wire, mesh, curved surfaces (e.g., coils) andthe like. In some embodiments, the insertion needle 190 that isinitially attached to the leads 112 is removed (e.g., cut off) once theleads 112 are secured at an appropriate position, such as the entry andexit point through the pleural membrane 200.

FIG. 2B is a diagram illustrating an example bipolar electrode lead 112having an insertion needle 190 according to an embodiment. Although onlya single lead 112 is shown in FIG. 2B for the sake of simplicity, itwill be understood that one or more leads 112 may be employed, with eachlead 112 being electrically coupled to the stimulator 100 at theproximal end and connected to the insertion needle 190 at the distalend. In some embodiments, the insertion needle 190 is used to positionthe lead 112 and its corresponding stimulating surfaces 120 in proximityof the vagus nerve 130 and the insertion needle 190 is also configuredto be removed once the lead 112 and its corresponding stimulatingsurfaces 120 is implanted. For example, in one embodiment, the insertionneedle 190 is used for the initial placement of the one or more leads112 and then the insertion needle 190 is removed (e.g., cut off) afterthe leads 112 are secured.

In one embodiment, the insertion needle 190 is configured to guide thelead 112 and its corresponding stimulating surfaces 120 through thepleural membrane and around the vagus nerve. As will be discussed inmore detail below, in alternative embodiments, the lead 112 and itscorresponding stimulating surfaces 120 may be positioned and secured onor near an external surface of the pleural membrane 209. Thus, incertain embodiments, the lead 112 and its corresponding stimulatingsurfaces 120 can be positioned and secured without insertion needle 190.

FIG. 2C is a diagram illustrating an example bipolar electrode lead 112having a cap 195 according to an embodiment. Although only a single lead112 is shown in FIG. 2C for the sake of simplicity, it will beunderstood that one or more leads 112 may be employed, with each lead112 being electrically coupled to the stimulator 100. In someembodiments, such as the one shown in FIG. 2C, a cap 195 can be placedon the terminal or distal end of each lead 112. The cap 195 may beapplied to the lead 112 prior to insertion of the lead 112 oralternatively may be applied to the lead 112 after the lead 112 has beenpositioned and secured. In one embodiment, the cap 195 is applied to thelead 112 after the lead 112 has been positioned and secured and theinsertion needle 190 has been removed.

FIG. 3A is a diagram illustrating an example placement of stimulatingsurface 120 near the vagus nerve 130 according to an embodiment.Although only a single lead 112 is shown in FIG. 3A for the sake ofsimplicity, it will be understood that one or more leads 112 may beemployed, with each lead 112 being electrically coupled to thestimulator 100 at its proximal end. In some embodiments describedherein, electric stimuli are applied to the vagus nerve 130 between thevagus nerve 130 and the pleural membrane 200 that surrounds the vagusnerve. In FIG. 3A, the stimulating surface 120 is inserted through thepleural membrane 200 and traverses a layer 210 of fat and connectivetissue surrounding the vagus nerve 130. In various embodiments, thestimulating surfaces 120 are placed in an appropriate position on ornear the vagus nerve 130. As FIG. 3A illustrates, the stimulatingsurfaces 120 are positioned between the vagus nerve 130 and the pleuralmembrane 200. In one embodiment, the stimulating surfaces 120 arepositioned closer to the vagus nerve 130 than the pleural membrane 200.In one embodiment, the stimulating surfaces 120 are placed as close tothe vagus nerve 130 as possible. In an embodiment where the stimulatingsurfaces 120 are positioned between the vagus nerve 130 and an innersurface of the pleural membrane 200, the size of each stimulatingsurface 120 can be relatively smaller with a smaller overall surfacearea of the stimulating surface 120 because the electrical stimuli doesnot need to penetrate the tissue of the pleural membrane 200 in order tostimulate the vagus nerve 130.

FIG. 3A further shows that the leads 112 are secured to the pleuralmembrane 200 at one or both of the entry site and exit site. Differenttypes of fastening means 230 can be used in the various embodimentsdescribed herein (e.g., suture, surgical clips, barbs, coils, mesh,corkscrew wire, and the like).

FIG. 3B is a diagram illustrating an example placement of stimulatingsurface 120 near the vagus nerve 130 according to an embodiment.Although only a single lead 112 is shown in FIG. 3B for the sake ofsimplicity, it will be understood that one or more leads 112 may beemployed, with each lead 112 being electrically coupled to thestimulator 100 at its proximal end. As depicted in FIG. 3B, the vagusnerve 130 is surrounded by the pleural membrane 200. In someembodiments, branches of the vagus nerve 130 are stimulated beneath thepleural membrane 200. In one embodiment, the leads 112 and stimulatingsurfaces 120 of an electrode 110, such as a securable-wire electrode orbipolar electrode or epimysial electrode or fascial electrode, areinserted through the pleural membrane. FIG. 3B depicts the hammockposition, wherein the leads 112 are placed under and around the vagusnerve 130. In various embodiments, the hammock position is used in orderto better maintain the position of the stimulating surfaces 120 proximalto the vagus nerve 130. In some embodiments, an insertion needle, suchas the one depicted in FIG. 2, is used to guide the leads 112 and theircorresponding stimulating surfaces 120 into and out of the pleuralmembrane 200, and to help place the stimulating surfaces 120 in anappropriate position. For example, to achieve the placement desired forthe hammock position, the insertion needle first enters the pleuralmembrane 200 at a first side of the vagus nerve 130, then travelsbeneath and around a second side vagus nerve 130 opposite the first sideof the vagus nerve 130, and finally exits the pleural membrane 200 onsubstantially the same first side of the vagus nerve 130 where theinsertion needle entered the pleural membrane 200. In some embodiments,the entry and exit points on the pleural membrane 200 for the leads 112are an appropriate distance apart. For example, the leads 112 may enterand exit the pleural membrane 200 at least 2 cm apart. In someembodiments, the stimulating surfaces 120 are placed within closeproximity of the vagus nerve 130. For example, in FIG. 3B, thestimulating surfaces 120 are placed according to the hammock positionand are therefore positioned beneath the vagus nerve relative to theentry and exit points of the leads 112 through the pleural membrane 200.In other embodiments, the stimulating surfaces 120 are placed along thetop or sides of the vagus nerve 130 relative to the entry and exitpoints of the leads 112 through the pleural membrane 200. In variousembodiments, the stimulating surfaces 120 are placed as close to thevagus nerve 130 as possible. In an embodiment where the stimulatingsurfaces 120 are positioned between the vagus nerve 130 and an innersurface of the pleural membrane 200, the size of each stimulatingsurface 120 can be relatively smaller with a smaller overall surfacearea of the stimulating surface 120 because the electrical stimuli doesnot need to penetrate the tissue of the pleural membrane 200 in order tostimulate the vagus nerve 130.

FIG. 3C is a diagram illustrating an example placement of stimulatingsurface 120 near the vagus nerve 130 according to an embodiment.Although only a single lead 112 is shown in FIG. 3C for the sake ofsimplicity, it will be understood that one or more leads 112 may beemployed, with each lead 112 being electrically coupled to thestimulator 100 at its proximal end. As shown in FIG. 3C, the leads 112and stimulating surfaces 120 may be positioned on and secured directlyto an exterior surface of the pleural membrane 200. In certain areas ofthe human body, such as in the upper thorax, the pleural membrane 200 issituated within close proximity of the vagus nerve 130. For instance,the fat and tissue layer 210 between the pleural membrane 200 and thevagus nerve 130 can be minimal in this location. Thus, in certainembodiments, the stimulating surfaces 120 do not need to be insertedthrough the pleural membrane 200 in order to position the stimulatingsurfaces 120 close enough to the vagus nerve 130 to expose the vagusnerve 130 to adequate electric stimuli. FIG. 3C shows that the leads 112and corresponding stimulating surfaces 120 are placed on and secured tothe pleural membrane 200 without penetrating its surface. Additionally,the stimulating surfaces 112 remain outside the pleural membrane 200. Insome embodiments, the vagus nerve 130 is stimulated through the pleuralmembrane 200 while the leads 112 and corresponding stimulating surfaces120 are placed and secured without penetrating the pleural membrane 200.In some embodiments, avoiding the insertion of the leads 112 andcorresponding stimulating surfaces 120 through the pleural membrane 200expedites and simplifies the implantation process. In an embodimentwhere the stimulating surfaces 120 are positioned on or near the outsidesurface of the pleural membrane 200, the size of each stimulatingsurface 120 can be relatively larger with a larger overall surface areaof the stimulating surface 120 because the electrical stimuli needs topenetrate the tissue of the pleural membrane 200 in order to stimulatethe vagus nerve 130.

FIG. 3D is a diagram illustrating an example placement of stimulatingsurface 120 near the vagus nerve 130 according to an embodiment.Although only a single lead 112 is shown in FIG. 3D for the sake ofsimplicity, it will be understood that one or more leads 112 may beemployed, with each lead 112 being electrically coupled to thestimulator 100 at its proximal end. Some of the embodiments describedherein are directed towards the use of leads 112 where the stimulatingsurfaces 120 are located on the distal tips of the leads 112. In someembodiments, needle electrodes 110 having a pointed or small disk shapestimulating surface 120 are used to stimulate the vagus nerve 130. Insome embodiments, the vagus nerve 130 is stimulated using needleelectrodes 110 that are insulated except for regions or areas around thedistal tip of the leads 112. As shown in FIG. 3D, the lead 112 comprisesa tip 240 and a corresponding stimulating surface 120 that togethercomprise a needle-like structure. The needle-like structure is insertedthrough the pleural membrane 130 such that the stimulating surface 120at the distal tip of the lead 112 is positioned near the vagus nerve130.

In some embodiments, such as shown in FIGS. 3A, 3B, and 3D, the vagusnerve 130 is stimulated by applying electric stimuli between the vagusnerve 130 and the pleural membrane 200. In other embodiments, such asshown in FIG. 3C, the vagus nerve 130 is stimulated by applying electricstimuli through the pleural membrane 200. Although not shown in FIG. 3D,it is understood that in cases where the vagus nerve 130 is sufficientlyclose to the pleural membrane 200 (e.g., minimal intervening fat andconnective tissue layer 210), the needle electrodes 110 may not fullypenetrate the pleural membrane 200. Otherwise stated, in someembodiments, the vagus nerve is stimulated by needle electrodes 110 thatare placed substantially on top of the pleural membrane 200 and securedto the pleural membrane 200 by fasteners 230. In an embodiment where thestimulating surfaces 120 are positioned between the vagus nerve 130 andan inner surface of the pleural membrane 200, the size of eachstimulating surface 120 can be relatively smaller with a smaller overallsurface area of the stimulating surface 120 because the electricalstimuli does not need to penetrate the tissue of the pleural membrane200 in order to stimulate the vagus nerve 130. However, in an embodimentwhere the stimulating surfaces 120 are positioned on or near the outsidesurface of the pleural membrane 200, the size of each stimulatingsurface 120 can be relatively larger with a larger overall surface areaof the stimulating surface 120 because the electrical stimuli needs topenetrate the tissue of the pleural membrane 200 in order to stimulatethe vagus nerve 130.

In one embodiment, when the stimulating surface 120 is positionedbetween the vagus nerve 130 and the inner surface of the pleuralmembrane 200, a wire electrode or needle electrode is employed. In analternative embodiment, when the stimulating surface 120 is positionedon or near the outer surface of the pleural membrane 200, a plate orfascial or epimysial electrode is employed.

In one embodiment, when the leads 112 and corresponding stimulatingsurfaces 120 are positioned adjacent to the vagus nerve 130, thestimulating surfaces 120 may be on the top or bottom or medial orlateral sides of the vagus nerve 130. In one embodiment, a laterallocation relative to the vagus nerve 130 may be beneficial to reduce therisk of atrial arrhythmia due to stimulation.

FIG. 4 is a diagram illustrating an example upper portion of theglossopharyngeal, vagus, and accessory nerves according to anembodiment. As depicted in FIG. 4, several branches of the vagus nerveextend to the heart. However, sympathetic nerve fibers are found nearthe main trunk of the vagus nerve. Thus, some of the embodimentsdescribed herein are directed toward stimulation of the branches of thevagus nerve. In some embodiments, stimulator 100 is used to stimulatebranches of the vagus nerve. In particular, in certain embodiments,stimulator 100 is used to stimulate the caudal cardiac branch of thevagus nerve. FIG. 4 further shows that stimulation of the vagus nerve inone embodiment takes place below the recurrent laryngeal nervebifurcation 500. In particular, some of the embodiments described hereinare directed towards stimulating the vagus nerve below the laryngealnerve bifurcation 500 as heart failure therapy, since application ofelectric stimuli to that site is associated with minimal complicationsand side effects. In some embodiments, an apparatus (e.g., stimulator100) is used to stimulate the vagus nerve below the laryngeal nervebifurcation 500 in order to induce desired vagal effects, such as adecrease in heart rate. In some embodiments, electric stimuli areapplied to the vagus nerve at any location 510 distal to the laryngealnerve bifurcation 500. In some embodiments, a precise point on the vagusnerve 130 below the laryngeal nerve bifurcation 500 where electricstimuli are optimally applied is determined on an individual basis. Forexample, depending on the individual patient, the vagus nerve 130 can beoptimally stimulated at a location that is between 1 cm and 10 cm below(caudal or distal to) the laryngeal nerve bifurcation 500.

FIG. 5 is a block diagram illustrating an example wired or wirelessprocessor enabled device 550 that may be used in connection with variousembodiments described herein. For example the system 550 may be usedwith the stimulator 100, as previously described with respect to FIG. 1.The system 550 can be a conventional personal computer, computer server,personal digital assistant, smart phone, tablet computer, or any otherprocessor enabled device that is capable of wired or wireless datacommunication. Other computer systems and/or architectures may be alsoused, as will be clear to those skilled in the art.

System 550 preferably includes one or more processors, such as processor560. Additional processors may be provided, such as an auxiliaryprocessor to manage input/output, an auxiliary processor to performfloating point mathematical operations, a special-purpose microprocessorhaving an architecture suitable for fast execution of signal processingalgorithms (e.g., digital signal processor), a slave processorsubordinate to the main processing system (e.g., back-end processor), anadditional microprocessor or controller for dual or multiple processorsystems, or a coprocessor. Such auxiliary processors may be discreteprocessors or may be integrated with the processor 560.

The processor 560 is preferably connected to a communication bus 555.The communication bus 555 may include a data channel for facilitatinginformation transfer between storage and other peripheral components ofthe system 550. The communication bus 555 further may provide a set ofsignals used for communication with the processor 560, including a databus, address bus, and control bus (not shown). The communication bus 555may comprise any standard or non-standard bus architecture such as, forexample, bus architectures compliant with industry standard architecture(“ISA”), extended industry standard architecture (“EISA”), Micro ChannelArchitecture (“MCA”), peripheral component interconnect (“PCI”) localbus, or standards promulgated by the Institute of Electrical andElectronics Engineers (“IEEE”) including IEEE 488 general-purposeinterface bus (“GPIB”), IEEE 696/S-100, and the like.

System 550 preferably includes a main memory 565 and may also include asecondary memory 570. The main memory 565 provides storage ofinstructions and data for programs executing on the processor 560. Themain memory 565 is typically semiconductor-based memory such as dynamicrandom access memory (“DRAM”) and/or static random access memory(“SRAM”). Other semiconductor-based memory types include, for example,synchronous dynamic random access memory (“SDRAM”), Rambus dynamicrandom access memory (“RDRAM”), ferroelectric random access memory(“FRAM”), and the like, including read only memory (“ROM”).

The secondary memory 570 may optionally include a internal memory 575and/or a removable medium 580, for example a floppy disk drive, amagnetic tape drive, a compact disc (“CD”) drive, a digital versatiledisc (“DVD”) drive, etc. The removable medium 580 is read from and/orwritten to in a well-known manner. Removable storage medium 580 may be,for example, a floppy disk, magnetic tape, CD, DVD, SD card, etc.

The removable storage medium 580 is a non-transitory computer readablemedium having stored thereon computer executable code (i.e., software)and/or data. The computer software or data stored on the removablestorage medium 580 is read into the system 550 for execution by theprocessor 560.

In alternative embodiments, secondary memory 570 may include othersimilar means for allowing computer programs or other data orinstructions to be loaded into the system 550. Such means may include,for example, an external storage medium 595 and an interface 570.Examples of external storage medium 595 may include an external harddisk drive or an external optical drive, or and external magneto-opticaldrive.

Other examples of secondary memory 570 may include semiconductor-basedmemory such as programmable read-only memory (“PROM”), erasableprogrammable read-only memory (“EPROM”), electrically erasable read-onlymemory (“EEPROM”), or flash memory (block oriented memory similar toEEPROM). Also included are any other removable storage media 580 andcommunication interface 590, which allow software and data to betransferred from an external medium 595 to the system 550.

System 550 may also include an input/output (“I/O”) interface 585. TheI/O interface 585 facilitates input from and output to external devices.For example the I/O interface 585 may receive input from a keyboard ormouse and may provide output to a display. The I/O interface 585 iscapable of facilitating input from and output to various alternativetypes of human interface and machine interface devices alike. The I/Ointerface 585 may also be adapted to generate electrical stimuli andsend the electrical stimuli to one or more electrodes (not shown) fordelivery to stimulating surfaces (not shown). The I/O interface 585 maygenerate electrical stimuli from an internal or external power sourcesuch as a battery (now shown) or power supply (not shown) connected toan electrical grid.

System 550 may also include a communication interface 590. Thecommunication interface 590 allows software and data to be transferredbetween system 550 and external devices (e.g. printers), networks, orinformation sources. For example, computer software or executable codemay be transferred to system 550 from a network server via communicationinterface 590. Examples of communication interface 590 include a modem,a network interface card (“NIC”), a wireless data card, a communicationsport, a PCMCIA slot and card, an infrared interface, and an IEEE 1394fire-wire, just to name a few. The communication interface 590advantageously can receive instructions regarding the parameters forelectrical stimuli to be generated by the I/O interface 585. Suchparameters may include but are not limited to the stimulating frequency,current amperage and duration, just to name a few.

Communication interface 590 preferably implements industry promulgatedprotocol standards, such as Ethernet IEEE 802 standards, Fiber Channel,digital subscriber line (“DSL”), asynchronous digital subscriber line(“ADSL”), frame relay, asynchronous transfer mode (“ATM”), integrateddigital services network (“ISDN”), personal communications services(“PCS”), transmission control protocol/Internet protocol (“TCP/IP”),serial line Internet protocol/point to point protocol (“SLIP/PPP”), andso on, but may also implement customized or non-standard interfaceprotocols as well.

Software and data transferred via communication interface 590 aregenerally in the form of electrical communication signals 605. Thesesignals 605 are preferably provided to communication interface 590 via acommunication channel 600. In one embodiment, the communication channel600 may be a wired or wireless network, or any variety of othercommunication links. Communication channel 600 carries signals 605 andcan be implemented using a variety of wired or wireless communicationmeans including wire or cable, fiber optics, conventional phone line,cellular phone link, wireless data communication link, radio frequency(“RF”) link, or infrared link, just to name a few.

Computer executable code (i.e., computer programs or software) is storedin the main memory 565 and/or the secondary memory 570. Computerprograms can also be received via communication interface 590 and storedin the main memory 565 and/or the secondary memory 570. Such computerprograms, when executed, enable the system 550 to perform the variousfunctions of the present invention as previously described.

In this description, the term “computer readable medium” is used torefer to any non-transitory computer readable storage media used toprovide computer executable code (e.g., software and computer programs)to the system 550. Examples of these media include main memory 565,secondary memory 570 (including internal memory 575, removable medium580, and external storage medium 595), and any peripheral devicecommunicatively coupled with communication interface 590 (including anetwork information server or other network device). Thesenon-transitory computer readable mediums are means for providingexecutable code, programming instructions, and software to the system550.

In an embodiment that is implemented using software, the software may bestored on a computer readable medium and loaded into the system 550 byway of removable medium 580, I/O interface 585, or communicationinterface 590. In such an embodiment, the software is loaded into thesystem 550 in the form of electrical communication signals 605. Thesoftware, when executed by the processor 560, preferably causes theprocessor 560 to perform the inventive features and functions previouslydescribed herein.

The system 550 also includes optional wireless communication componentsthat facilitate wireless communication over a voice and over a datanetwork. The wireless communication components comprise an antennasystem 610, a radio system 615 and a baseband system 620. In the system550, radio frequency (“RF”) signals are transmitted and received overthe air by the antenna system 610 under the management of the radiosystem 615.

In one embodiment, the antenna system 610 may comprise one or moreantennae and one or more multiplexors (not shown) that perform aswitching function to provide the antenna system 610 with transmit andreceive signal paths. In the receive path, received RF signals can becoupled from a multiplexor to a low noise amplifier (not shown) thatamplifies the received RF signal and sends the amplified signal to theradio system 615.

In alternative embodiments, the radio system 615 may comprise one ormore radios that are configured to communicate over various frequencies.In one embodiment, the radio system 615 may combine a demodulator (notshown) and modulator (not shown) in one integrated circuit (“IC”). Thedemodulator and modulator can also be separate components. In theincoming path, the demodulator strips away the RF carrier signal leavinga baseband receive audio signal, which is sent from the radio system 615to the baseband system 620.

If the received signal contains audio information, then baseband system620 decodes the signal and converts it to an analog signal. Then thesignal is amplified and sent to a speaker. The baseband system 620 alsoreceives analog audio signals from a microphone. These analog audiosignals are converted to digital signals and encoded by the basebandsystem 620. The baseband system 620 also codes the digital signals fortransmission and generates a baseband transmit audio signal that isrouted to the modulator portion of the radio system 615. The modulatormixes the baseband transmit audio signal with an RF carrier signalgenerating an RF transmit signal that is routed to the antenna systemand may pass through a power amplifier (not shown). The power amplifieramplifies the RF transmit signal and routes it to the antenna system 610where the signal is switched to the antenna port for transmission.

The baseband system 620 is also communicatively coupled with theprocessor 560. The central processing unit 560 has access to datastorage areas 565 and 570. The central processing unit 560 is preferablyconfigured to execute instructions (i.e., computer programs or software)that can be stored in the memory 565 or the secondary memory 570.Computer programs can also be received from the baseband processor 610and stored in the data storage area 565 or in secondary memory 570, orexecuted upon receipt. Such computer programs, when executed, enable thesystem 550 to perform the various functions of the present invention aspreviously described. For example, data storage areas 565 may includevarious software modules (not shown) that are executable by processor560.

Various embodiments may also be implemented primarily in hardware using,for example, components such as application specific integrated circuits(“ASICs”), or field programmable gate arrays (“FPGAs”). Implementationof a hardware state machine capable of performing the functionsdescribed herein will also be apparent to those skilled in the relevantart. Various embodiments may also be implemented using a combination ofboth hardware and software.

Furthermore, those of skill in the art will appreciate that the variousillustrative logical blocks, modules, circuits, and method stepsdescribed in connection with the above described figures and theembodiments disclosed herein can often be implemented as electronichardware, computer software, or combinations of both. To clearlyillustrate this interchangeability of hardware and software, variousillustrative components, blocks, modules, circuits, and steps have beendescribed above generally in terms of their functionality. Whether suchfunctionality is implemented as hardware or software depends upon theparticular application and design constraints imposed on the overallsystem. Skilled persons can implement the described functionality invarying ways for each particular application, but such implementationdecisions should not be interpreted as causing a departure from thescope of the invention. In addition, the grouping of functions within amodule, block, circuit or step is for ease of description. Specificfunctions or steps can be moved from one module, block or circuit toanother without departing from the invention.

Moreover, the various illustrative logical blocks, modules, and methodsdescribed in connection with the embodiments disclosed herein can beimplemented or performed with a general purpose processor, a digitalsignal processor (“DSP”), an ASIC, FPGA or other programmable logicdevice, discrete gate or transistor logic, discrete hardware components,or any combination thereof designed to perform the functions describedherein. A general-purpose processor can be a microprocessor, but in thealternative, the processor can be any processor, controller,microcontroller, or state machine. A processor can also be implementedas a combination of computing devices, for example, a combination of aDSP and a microprocessor, a plurality of microprocessors, one or moremicroprocessors in conjunction with a DSP core, or any other suchconfiguration.

Additionally, the steps of a method or algorithm described in connectionwith the embodiments disclosed herein can be embodied directly inhardware, in a software module executed by a processor, or in acombination of the two. A software module can reside in RAM memory,flash memory, ROM memory, EPROM memory, EEPROM memory, registers, harddisk, a removable disk, a CD-ROM, or any other form of storage mediumincluding a network storage medium. An exemplary storage medium can becoupled to the processor such the processor can read information from,and write information to, the storage medium. In the alternative, thestorage medium can be integral to the processor. The processor and thestorage medium can also reside in an ASIC.

The above description of the disclosed embodiments is provided to enableany person skilled in the art to make or use the invention. Variousmodifications to these embodiments will be readily apparent to thoseskilled in the art, and the generic principles described herein can beapplied to other embodiments without departing from the spirit or scopeof the invention. Thus, it is to be understood that the description anddrawings presented herein represent a presently preferred embodiment ofthe invention and are therefore representative of the subject matterwhich is broadly contemplated by the present invention. It is furtherunderstood that the scope of the present invention fully encompassesother embodiments that may become obvious to those skilled in the artand that the scope of the present invention is accordingly not limited.

1. An apparatus comprising: a stimulator configured to generate one ormore electric stimuli based at least in part on at least one stimulatingparameter; at least two leads, each of the at least two leads having aproximal end and a distal end, wherein the proximal end of each lead iselectrically connected to the stimulator; and at least one stimulatingsurface at the distal end of each of the at least two leads, wherein theat least one stimulating surface is configured to create an electricalfield in response to receiving the one or more electric stimuligenerated by the stimulator.
 2. The apparatus of claim 1, wherein the atleast two leads and the at least one stimulating surface are provided ascomponents of an open field bipolar electrode.
 3. The apparatus of claim2, wherein the open field bipolar electrode comprises one of anepimysial electrode, a fascial electrode, a needle electrode, a wireelectrode and a plate electrode.
 4. The apparatus of claim 1, whereinthe at least two leads are configured to be secured to a pleuralmembrane of a subject using one or more of the following: sutures;surgical clips; surgical glue; barbs; coils; mesh; or corkscrew wire. 5.The apparatus of claim 4, further comprising said one or more of thefollowing: sutures; surgical clips; surgical glue; barbs; coils; mesh;or corkscrew wire.
 6. The apparatus of claim 1, wherein the at least onestimulating parameter comprises an electric pulse frequency selectedfrom a range of 3 Hertz to 20 Hertz.
 7. The apparatus of claim 1,wherein the at least one stimulating parameter comprises an electricpulse duration selected from a range of 200 μs to 1000 μs.
 8. Theapparatus of claim 1, wherein the at least one stimulating parametercomprises an electric current amperage selected from a range of 1 mA to12 mA.
 9. The apparatus of claim 1, wherein the at least one stimulatingparameter comprises a duty cycle having a 10 second ON period and a 5second OFF period.
 10. The apparatus of claim 1, wherein the at leastone stimulating parameter comprises a duty cycle comprising an ON periodof up to 24 hours and an OFF period between 1 second to 2000 seconds.11. The apparatus of claim 1, wherein each stimulating surface of the atleast one stimulating surface is between 0.5 mm to 5 mm in length andbetween 0.5 mm and 1.5 mm in width.
 12. The apparatus of claim 1, eachstimulating surface of the at least one stimulating surface is between0.5 mm to 5 mm in length and 0.5 mm to 5 mm in width.
 13. The apparatusof claim 1, wherein the at least two leads comprise a first lead and asecond lead, wherein the at least one stimulating surface at the distalend of the first lead comprises a first stimulating surface, and whereinthe at least one stimulating surface at the distal end of the secondlead comprises a second stimulating surface that is positioned 1 mm to 5mm away from the first stimulating surface.
 14. The apparatus of claim1, wherein each of the at least two leads comprises a conducting wirethat is at least partially surrounded by an insulating surface, andwherein each stimulating surface of the at least one stimulating surfaceat the distal end of each lead is formed at an exposed area where theconducting wire is not covered by the insulating surface.
 15. Theapparatus of claim 14, wherein the conducting wire comprises platinum.16. The apparatus of claim 1, further comprising at least two insertionneedles, wherein the distal end of each lead of the at least two leadsis coupled to a respective insertion needle of the at least twoinsertion needles.
 17. The apparatus of claim 1, further comprising atleast two caps, wherein each cap of the at least two caps is placed onthe distal end of a respective lead of the at least two leads.